I. Field of the Invention
The present invention concerns transdermal delivery of therapeutic agents by the use of skin worn devices. More particularly, the invention is directed to a system that is wearable and utilizes the principle of iontophoresis as a means of introducing substances into the body. The system is packaged as a self-contained easily activated system in the form of a rather small skin worn patch that contains electrodes and a therapeutic agent. When applied to the skin, the system completes a circuit and can initiate a flow and controlled duration of current corresponding to the desired rate and amount of therapeutic agent to be delivered.
II. Related Art
The process of iontophoresis was described by LeDuc in 1908, and has since found commercial use in the delivery of ionically charged compounds such as pilocarpine, dexamethasone, and lidocaine. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode, while ions bearing a negative charge are driven across the skin at the site of an electrolytic electrical system cathode.
With iontophoretic devices, the application time and level of current flow (usually reported in units of milli-amp minutes) between the anode and cathode is directly correlated to the amount of drug delivered. The efficiency of drug delivery in an iontophoretic system can be measured by the proportion of current carried by drug molecules, relative to the current carried by competing non-medication ions having the same charge as the medication.
Iontophoresis devices conventionally have included two electrodes attached to a patient, each connected via a wire to a microprocessor controlled electrical instrument. Medication is placed under one or both of the electrodes, for delivery into the body as the instrument is activated. The instrument is designed to regulate current flow and application time. Examples of such instruments are described in U.S. Pat. Nos. 5,254,081, and 5,431,625. Power for these devices is usually provided by DC batteries, which when providing power for the microprocessor controlled circuitry allow application of a voltage to the electrodes to create a regulated current flow. These microprocessor systems are disadvantaged by the fact that patients are xe2x80x98attached by wirexe2x80x99 to an instrument, which limits patient mobility and ability to conduct normal daily activities. A typical application period for creation of skin anesthesia is approximately 10-20 minutes, which consumes instrument, caregiver, and patient time.
More recently, wearable iontophoretic systems have been developed in which the electrical circuitry and power supplied are integrated into a single patch. These systems are advantageous in that they do not have external wires, and they are much smaller in size. Examples of such systems can be found in U.S. Pat. Nos. 5,358,483; 5,458,569; 5,466,217; 5,605,536; and 5,651,768.
Typically, drug ions are delivered into the body from an aqueous xe2x80x98drugxe2x80x99 reservoir contained in the iontophoretic device, and counter ions of opposite charge are delivered from a xe2x80x98counterxe2x80x99 reservoir. A critical step in iontophoresis involves the process for incorporation of drug ions and counter ions into the device. It is well know that if such a device is improperly loaded, the device will not perform as desired.
Most often, drug/ion solutions are stored remotely in bulk quantity and introduced to an absorbent layer of the iontophoresis electrode at the time of use. Examples of such systems are described in U.S. Pat. Nos. 5,087,241; 5,087,242; 5,846,217; and 6,421,561. An advantage to this approach is that the electrodes are packaged and stored in a dry state, which is optimal for shelf life. A disadvantage to this approach is that the electrodes can be easily over-filled or under-filled, thus this aspect requires trained personnel with good technique. Additionally, because the drug solution is stored separately from the electrodes, management of two inventories is required.
To avoid the need for users to incorporate the aqueous drug or ion reservoir at the time of use, the drug solution can be pre-packaged into the electrode. Unfortunately, this inevitably reduces shelf life. During storage, moisture emanating from the drug solution can be absorbed into adjacent materials, resulting in corrosion of metallic components, degradation of power sources, and inadequate hydration of the drug pad. U.S. Pat. Nos. 5,738,647 and 5,817,044 discloses a device where an aqueous reservoir is stored in contact with an electrode assembly, and a dry medicament layer introduced to the aqueous reservoir at the time of use. Unfortunately, with this configuration the electrode is still stored in wet environment, and is therefore susceptible to corrosive deterioration.
In U.S. Pat. No. 5,685,837, a system is described in which a drug of interest, in a dry form, is pre-packaged into the electrode(s). This offers two advantages. First, moisture is not present to compromise the integrity of metallic electrode components during storage, and second, the drug of interest remains very stable. This offers a particular advantage for the delivery of certain drugs, such as large polypeptides, which have a poor stability in solution form. However, this approach requires a moisture activation step at the time of use, which can involve a time delay or introduce a reason for mechanistic failure.
Many patents describe systems where drug solutions are co-packaged with the iontophoretic device, but positioned apart from the electrodes and other metallic components until an xe2x80x98activationxe2x80x99 step is implemented at the time of use. U.S. Pat. Nos. 5,158,537; 5,288,289; 5,310,404; 5,320,598; 5,385,543; 5,645,527; 5,730,716; and 6,223,075 describe such devices. In these devices, a co-packaged electrolyte constituent liquid is stored remotely from the electrodes, in a rupturable container and a mechanical action step at the time of use induces a fluid transfer to a receiving reservoir adjacent to the electrodes. These systems enable precise fluid volumes to be incorporated at the time of manufacture to avoid overfilling; however, these devices are mechanically complex, and can fail if, for example, the package is squeezed during shipping, the container breaks and fluids are pre-maturely released. Other failure modes include compromising of the fluid delivery path during storage, if for example, outgassing hydrophobic plasticizer material is absorbed into the fluid channel, inhibiting the transfer of fluid at the time of use.
Another strategy to incorporate drug into the iontophoretic device is described in U.S. Pat. No. 4,383,529. In that disclosure, a preformed gel containing the drug is transferred into an electrode receptacle at the time of use. The advantages of this system include the provision of a precise pre-determined volume of drug gel to prevent over-filling, and the fact that using the gel form of the drug matrix insures that liquid will not xe2x80x98leakxe2x80x99 during storage or transfer. A significant disadvantage to the device described, however, exists because the user is required to visually align the gel into the receptacle at the time of use, which is a process that may be difficult for elderly patients. Additionally, that device requires the user to apply a mucilage material to the electrode prior to incorporating the gel so as to insure the integrity of the electrical contact between the electrode and the drug gel. Furthermore, it is necessary at the time of use to rotate the gel over the mucilage layer to remove entrapped air, which introduces another technique-dependant source of error. Finally, the gels of interest are stored separately from the electrodes in a plastic bag, or the like, and this requires management and storage of two separate components.
Thus, while there exists a variety of devices in the class, each of which has certain attributes, there remains a need for a single iontophoretic drug delivery system that combines the desired attributes and eliminates the drawbacks recited above. The present invention provides such a device in the form of an iontophoretic drug delivery system that is reliable, self-contained, simple to use, and shelf-stable.
The present invention solves many of the problems associated with prior self-contained iontophoretic drug delivery systems by the provision of a reliable, selfcontained system which enjoys a long stable shelf life and which is also quite easy to use. The present invention contemplates a wearable iontophoretic device that is prepackaged as a complete self-contained unit which includes the active species or drug to be administered and counter ions. The system includes a provision for isolating moisture sources from the electrodes and from the power source during storage to optimize shelf stability. The inventive system provides a simple, user-friendly mechanism to transfer the drug to be administered and counter ion reservoirs to the electrodes in order to activate the device circuit. The self-contained iontophoretic drug delivery system of the present invention contemplates the storage of all elements of the device in a single device to be activated in a single outer package. Depending on the drug or other therapeutic active species to be administered, the particular ion species may be selectively or optionally stored in either a dry state or a wet state in order to optimize shelf stability.
It is an important aspect of the present invention that it provides a complete, self-contained packaged device that includes all of the components necessary for iontophoretic delivery, including a wearable device; an aqueous anodic matrix; and an aqueous cathodic matrix. All three components (as stored) are carried on a thin, planar substrate, which additionally serves as a release liner, that is removed during device activation. No external components need to be included. If the active species or drug to be delivered is of a positive charge, it is associated with the anodic electrode, if the drug to be delivered is of a negative charge, it is associated with the cathodic electrode.
The entire device including the substrate and its components are packaged together, preferably in a conventional medical foil storage pouch or the like (not shown in figures). Within the foil pouch, the cathodic and anodic aqueous matrixes are each isolated from the iontophoretic device by a water impermeable release membrane which is peeled away and removed at the time of activation. In the event that the drug to be delivered remains stable when dissolved in an aqueous solution, the drug is incorporated into the appropriate aqueous matrix at the time of manufacture. If, however, the drug has a limited shelf stability when dissolved, the drug is incorporated as a dry layer adjacent the related electrode of the iontophoretic device, and dissolved into the aqueous matrix at the time of activation.
The activation and placement of the device is rapid and simple. First, the sealed storage pouch is breached revealing the substrate and its three components with the cathodic and anodic aqueous matrices remaining isolated from the iontophoretic device separated by the water impermeable membranes indicated above. To activate the device, water impermeable membrane covers which isolate the cathodic and anodic aqueous matrices are simply peeled away and removed. The substrate is then folded inward on itself at predetermined locations to engage the aqueous matrices with the iontophoretic device. For this purpose, one or more clearly visible fold lines are preferably provided on the substrate to insure proper alignment as the device is folded. An adhesive material provided on the iontophoretic device serves to secure the aqueous matrices to the device as they are engaged during the folding step. Engagement of the aqueous matrices, activates the device and the then activated device can be removed from the substrate or release liner ply and be placed on the body to begin drug delivery.
A key element to this invention is the ease of successful transfer of the anodic and cathodic aqueous matrices to the iontophoretic device at the time of activation which is facilitated by the incorporation of fold lines (which may be score lines, perforations or the like) that insure proper folded alignment. Additionally, the matrices need to be kept in place during the act of folding the substrate. While this can be accomplished in various ways, preferably a minor amount of releasing packaging adhesive material is provided to hold the matrices in place. Alternatively, they may be held in place without adhesives by containment in a recessed portion provided in the substrate. Successful transfer of the matrix to the iontophoretic device requires that an adhesive present on the surface of the receiving device (transfer adhesive) form a bond that is stronger than that of the packaging adhesive material that fixed the matrices to the release liner or substrate. It has also been found that the adhesive material on the iontophoretic device should ideally surround at least a portion of the electrode, so as to maintain adequate contact between the electrode and matrix during the iontophoresis process.